DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE Diabetes Metab Res Rev 2014; 30: 543–553. Published online 12 August 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2573

Diabetes mellitus: influences on cancer risk

Leszek Szablewski* Chair of General Biology and Parasitology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland *Correspondence to: Leszek Szablewski, Chair of General Biology and Parasitology, Center of Biostructure Research, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland. E-mail: [email protected]

Summary Diabetes mellitus and cancer are common conditions, and their co-diagnosis in the same individual is not infrequent. The relative risks associated with type 2 diabetes are greater than twofold for hepatic, pancreatic, and endometrial cancers. The relative risk is somewhat lower, at 1.2–1.5-fold for colorectal, breast, and bladder cancers. In comparison, the relative risk of lung cancer is less than 1. The evidence for other malignancies (e.g. kidney, non-Hodgkin lymphoma) is inconclusive, whereas prostatic cancer occurs less frequently in male patients with diabetes. The potential biologic links between the two diseases are incompletely understood. Evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer. Whereas anti-diabetic drugs have a minor influence on cancer risk, drugs used to treat cancer may either cause diabetes or worsen pre-existing diabetes. If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenous administered insulin. Obtained results showed that patients with type 1 diabetes had elevated risks of cancers of the stomach, cervix, and endometrium. Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes. Copyright © 2014 John Wiley & Sons, Ltd. Keywords

diabetes mellitus; cancer; insulin; glucose-lowering therapies

Introduction

Received: 10 September 2012 Revised: 11 March 2013 Accepted: 19 March 2013

Copyright © 2014 John Wiley & Sons, Ltd.

Diabetes mellitus and cancer are common conditions, and their co-diagnosis in the same individual is not infrequent. As early as 1932, physicians noticed an apparent association between type 2 diabetes and increased cancer risk [1], but only in the past decade has significant epidemiological evidence been amassed to suggest that diabetes and cancer are associated, and the link appears causal [2]. According to Seewoodhary and Bain [3], the relative risks associated with type 2 diabetes are greater than twofold for liver, pancreatic, and endometrial cancers. Mentioned authors observed that the relative risk is somewhat lower, at 1.2–1.5-fold for colorectal, breast, and bladder cancers. On the other hand, the relative risk of lung cancer is less than 1, and the evidence for others (e.g. kidney and non-Hodgkin lymphoma) is inconclusive, whereas prostatic cancer occurs less frequently in patients with diabetes [3]. But potential biologic links between the two diseases are incompletely understood.

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Although it is widely recognize that diabetes is associated with a high a risk of cardiovascular and microvascular complications, it is well recognized that the condition is also associated with an increased risk of cancer. There are observations suggesting that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer. Whereas anti-diabetic drugs have a minor influence on cancer risk, drugs used to treat cancer may either cause diabetes or worsen pre-existing diabetes [4]. It is unknown whether the excess mortality associated with diabetes in cancer patients is greater than the excess mortality observed amongst diabetic patients without cancer. Meta-analysis suggests that diabetes is associated with an increased mortality compared with normoglycemic individuals across all cancer types particularly in patients with cancers of endometrium, breast, and colorectum [5]. It is suggested that diabetes is an independent predictor of mortality from cancer of the colon, pancreas, female breast, and in men, of the liver and bladder [6]. If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenous administered insulin. Results obtained by Zendehdel et al. [7] showed that patients with type 1 diabetes had elevated risks of cancers of the stomach, cervix, and endometrium. Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes (Table 1).

Diabetes and cancer risk Diabetes and liver cancer Liver is a key organ involved in the metabolic derangements typical of diabetes. Hepatocytes are exposed to higher insulin

concentrations than other tissues, a condition that is exacerbated in insulin-resistant hyperinsulinemic type 2 diabetic patients. Studies on liver cancer have been sparse, but a 1997 study out of Italy found that patients with types 1 and 2 diabetes had twice the risk of liver cancer, after adjusting for age, sex, alcohol and tobacco consumption, history of hepatitis and cirrhosis, body mass index (BMI), and history of liver cancer in first-degree relatives [25]. According to this research, a history of diabetes explains about 8% of cases of liver cancer in the population studied [25]. Several meta-analyses indicate that the strongest association between diabetes mellitus and increased cancer risk is with liver and pancreatic cancers. Most epidemiologic studies indicate a twofold to threefold increase in hepatocellular carcinomas of diabetic patients [8]. Many studies suggest a link between liver cancer and diabetes [26], which may be mediated through higher risk of non-alcoholic steatohepatitis, leading to cirrhosis and liver cancer [27]. According to Vigneri et al. [8], ‘increased liver cancer incidence in diabetes is well documented and, although the exact mechanisms underlying this association are still unclear, liver inflammation, hepatocyte damage, and repair are likely to be involved in the higher frequency of hepatocellular carcinomas among patients with diabetes’. Additional factors that may favour hepatocellular carcinomas in diabetes mellitus include hepatitis B and C, virus infections, both more frequent in diabetic patients as compared with the nondiabetic subjects [28,29].

Diabetes and pancreatic cancers Several meta-analyses indicate the strong association between diabetes mellitus and increased risk of pancreatic cancer. On the other hand, most earlier studies investigating the association between diabetes and pancreatic cancer are probably misleading because they do not distinguish between pre-existing diabetes and new-onset diabetes [30]. The following question was raised, ‘is diabetes

Table 1. Risk of selected cancers in type 1 and type 2 diabetes Type of diabetes Cancer risk with type 2 diabetes

Risk of cancer The relative risks of following cancers are ~ twofold A smaller increased risk, of 20–50% is seen for the following cancers The incidences of cancers are lower for people with type 2 diabetes (the inverse association between type 2 diabetes and cancer)

The cancers with increased risk in type 1 diabetes

Cancer

References

Liver Pancreatic Endometrial Colorectal Bladder Breast Blood (non-Hodgkin’s lymphoma) Prostate

[3,8] [3,9,10] [3,11,12] [13–16] [17] [18,19] [20,21] [22,23]

Stomach Cervical Endometriala

[7,24] [7,24] [12,24]

a

Long-term insulin therapy may be responsible for increased risk of endometrial cancer in diabetic women with type 1 diabetes [7].

Copyright © 2014 John Wiley & Sons, Ltd.

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mellitus a risk factor for pancreatic cancer?’ [25]. According to Volkers [25], ‘a 1997 Danish study found that diabetes came first. A 1998 American study found a small but persistent increased risk of death from pancreatic cancer in diabetic patients, and concluded that diabetes may be true, but modest, risk factor for pancreatic cancer. And the other study showed a 50% increased risk of pancreatic cancer in patients diagnosed with diabetes at least 10 years prior to a cancer diagnosis’. Studies of the relationship between diabetes mellitus and pancreatic cancer are complicated by the fact that diabetes has two major forms that are different entities in terms of pathophysiology [31]. Most epidemiological studies have not distinguished between type 1 and type 2 diabetes; however, obtained results have suggested that type 1 diabetes is not associated with an increased risk for pancreatic cancer [32,33] (Table 1). The new-onset diabetes may be a possible sign of pancreatic functional damage due to a still undiagnosed pancreatic cancer [30]. This situation is so frequent that hyperglycemia and diabetes, when appearing after the age 45–50 years, in a lean subject with no family history of diabetes, are considered sufficient to pose an indication for pancreatic cancer screening [34]. About 80% of pancreatic cancer patients have glucose intolerance or frank diabetes. The following questions were raised: what is a cause and what is an effect? Is diabetes due to pancreatic cancer or is diabetes a risk factor for the development of pancreatic cancer [35]? There are observations, and suggestions, that recently developed glucose intolerance or diabetes may be a consequence of pancreatic cancer. This suggestion is based on observations that (1) the majority of diabetes associated with pancreatic cancer is diagnosed either concomitantly with the cancer or during the 2 years before the cancer is found [36] and (2) 71% of the glucose intolerance found in pancreatic cancer patients is unknown before cancer is diagnosed [37]. A very important observation was performed by Permert et al. [38] that showed that insulin sensitivity and overall diabetic state in pancreatic cancer patients who undergo tumour resection are markedly improved 3 months after the surgery. The suggestion that pancreatic cancer causes diabetes was confirmed also by Basso et al. [39]. Mentioned authors found in pancreatic cancer patients a peptide that is considered to be a putative pancreatic cancer associated diabetic factor. There are also evidences for diabetes as risk factors for pancreatic cancer, especially relative risks associated with the different periods after the diagnosis of diabetes [35]. A relatively modest but persistent increased risk of death from pancreatic cancer was found, even when the diagnosis of diabetes preceded death by many years [40,41]. Silverman [42] has found a significant positive trend in risk with increasing years prior to diagnosis of cancer. On the other hand, there Copyright © 2014 John Wiley & Sons, Ltd.

are studies showed that diabetes is not a risk factor for pancreatic cancer [43]. As showed earlier, no simple answer to the question of which of the two hypotheses is right [35].

Diabetes and colorectal cancer Type 2 diabetes has been associated with an increased risk of colorectal cancer in most, but not all, studies [44,45]. Growing evidence shows that diabetes is associated with an increased risk of colorectal cancer compared with no diabetes [46]. The association did not differ significantly by sex or by cancer sub-site [47]. Obtained results showed that diabetes mellitus is positively associated with colorectal cancer mortality [6].

Diabetes and endometrial cancer Meta-analysis of 16 studies showed a significantly increased risk of endometrial cancer amongst women with diabetes [11]. This risk is independent from obesity as it persists even after correcting epidemiological data for this disease. A stronger association of type 1 diabetes and endometrial cancer was noted [47].

Diabetes and breast cancer Breast cancer is currently the most common cancer amongst women in industrialized countries. More than a century ago, hyperglycemia and diabetes were first linked to breast cancer. Since the 1950s, incidence reports have described women with breast cancer as having higher rates of diabetes than of healthy women [18]. In recent years, a growing number of data, both laboratory and clinical, suggest complex association between type 2 diabetes and breast cancer. Breast cancer and diabetes commonly occur together, and up to 16% of older breast cancer patients may suffer from diabetes [48]. Metaanalysis of 20 case-control study and cohort study has shown a statistical significant 20% increased risk of breast cancer [19]. It is interesting to note that risk of breast cancer is increased in women with diabetes, and this risk is independent from obesity, a well-established factor promoting breast cancer. A positive association between breast cancer mortality and diabetes was found in three out of five studies [19]. In the largest study, after adjusting for age, race, BMI, physical activity, smoking, and alcohol, a relative risk in women with diabetes was 1.27 in comparison with the nondiabetic female population [6]. For studies in which the association between a history of diabetes and the risk of breast cancer was analysed separately amongst postmenopausal women [49] Diabetes Metab Res Rev 2014; 30: 543–553. DOI: 10.1002/dmrr

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or amongst women of postmenopausal age [50], a stronger association between diabetes and breast cancer was observed in both case-control studies [51] and cohort studies [49] with an overall summary relative risk of 1.19 [18].

Diabetes and prostate cancer The association between diabetes and prostate cancer is controversial, with a number of studies suggesting positive and negative associations [52]. But, in contrast to the increased risk in numerous forms of neoplasia, most studies report a reduced risk of prostate cancer in men with diabetes. A recent meta-analysis showed a significant inverse association between diabetes and prostate cancer [53]. A meta-analysis that included 14 studies published between 1971 and 2002 showed a slight but significant reduction of risk to develop prostate cancer in diabetic patients, with a relative risk of about 1.91 [53]. This result was confirmed by a second meta-analysis: the relative risk was 0.84 [22].

Diabetes and bladder cancer As described by Chowdhury [47], meta-analysis of 16 studies showed increased risk of bladder cancer if compared with nondiabetic patients. Diabetic patients have a modestly increased risk of bladder cancer [17].

Diabetes and renal cancer In diabetic patients, the increased incidence and increased mortality for kidney cancer have been observed [54]. Unfortunately, numbers in these studies are small, and no meta-analysis has yet been performed [47].

L. Szablewski

circulating oestrogen levels, and increased breast cancer risk [59]. Obese postmenopausal women usually present an increase in both estrone and estradiol. Type 2 diabetes and associated adiposity may stimulate other cellular pathways leading to carcinogenesis [3]. Adipose tissue produces a number of cytokines, predominantly IL-6 that may play a causative role in regulating mitogenic activity. Adipose tissue is an active endocrine organ producing also free fatty acids, monocyte chemoattractant protein, plasminogen activator inhibitor-1 (PAI-1), adiponectin, leptin, and tumour necrosis factor-α [3,60] (Table 2). These factors might play an etiologic role in carcinogenesis, and in some cases, the role for these molecules is well known [56]. Animal studies showed that cancers are more aggressive in obese animals and indolent in lean animals [3,72]. A majority of studies suggest that diets low in red and processed meats and higher in vegetables, fruits, and whole grains are associated with a lower risk of many types of cancer [73]. It is suggested that diet-induced changes in IL-6 and/or insulin may mediate an effect of diet on carcinogenesis [3]. Evidence from meta-analysis suggests that diet high in fruits, whole grain cereals, monounsaturated fatty acids, and dietary fibre may even protect against type 2 diabetes, possibly through improving insulin sensitivity [74], and may even protect against cancer in type 2 diabetes [3,73]. It was observed that higher levels of physical activity are associated with a lower risk of colon, breast, and endometrial cancers [75] and may help prevent other cancers; however, a clear link has not been established. Link between physical activity and cancer is not difficult to explain, because higher physical activity is associated with a lower risk of diabetes. Smoking and alcohol consumption are independent risk factors for the development of diabetes [76,77], and therefore, there are risk factors for the development of cancer [56].

Risk factors that are common to both Possible biologic links between diabetes and cancer diabetes and cancer risk Over 80% of type 2 diabetic patients are obese. Obesity is associated with a higher incidence and a higher mortality in cancer [4]. Cancer mortality significantly increases with increasing patient BMI [55]. The cancers most consistently associated with overweight and obesity are colorectum, endometrium, pancreas, kidney, gallbladder, and liver [56]. A statistical significant positive association between diabetes mellitus and the risk of cancer remained in three of the studies [49,57,58]. Fat distribution in the body is also important. Central obesity is more harmful than gynoid obesity in terms of increased risk and worst cancer outcome [8]. A tight correlation has been observed between obesity, Copyright © 2014 John Wiley & Sons, Ltd.

Carcinogenesis is a complex process. The process of malignant transformation can be divided into multiple steps: initiation, promotion, and progression. Factors that affect one or more steps of this pathway could be associated with cancer incidence or mortality. Possible mechanisms for a direct link between diabetes and cancer include hyperinsulinemia, hyperglycemia, or chronic inflammation (Table 2). Hyperinsulinemia may be endogenous because of insulin resistance or exogenous due to administered insulin or insulin secretagogues. Insulin and the insulin-like growth factor (IGF) axis have a number of effects on cancer cells. Human tumours commonly over-express insulin receptors [78] Diabetes Metab Res Rev 2014; 30: 543–553. DOI: 10.1002/dmrr

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Diabetes Mellitus and Cancer Table 2. Possible biologic links between diabetes and cancer risk Risk factors Hyperinsulinemia

Hyperglycemia

Levels of plasma androgens and genetic mechanism

Obesity

Mechanisms of action

References

In the genesis of type 2 diabetes, reduced insulin sensitivity plays a key role, inducing compensatory hyperinsulinism with an increased level of circulating IGF-1, well known to stimulate cell proliferation in many organs, including the liver, pancreas, colon, ovary, and breast, the sites with an increased risk of cancer in type 2 diabetic patients. This effect is enhanced by the action of insulin in excess, to bind and to active the IGF-1 receptor. Insulin reduces the hepatic production of IGFBP-1 and IGFBP-2. This leads to increased levels of free-circulating biologically active IGF-1. This could act as a growth stimulus in cancer cells that express these receptors. Androgen synthesis in the ovaries is increased by hyperinsulinemia in premenopausal women (stimulation androgen synthesis in the ovarian stroma). High insulin levels may decrease the concentration of circulating sex-hormone-binding globulin. Elevated endogenous sex steroid levels are associated with a higher risk of postmenopausal cancers (breast and endometrial).

[18,61–63]

Hyperglycemia may influence on abnormal energy balance and impairing the effect of ascorbic acid on the intracellular metabolism. These abnormalities may reduce the effectiveness of the immune system. It is suggested a role for the oxidative stressresponsive genes that are sensitive to hyperglycemia and regulate the level of reactive oxygen species. Hyperglycemia may be responsible for excess glucose supply to cancer cells, resistance to apoptosis, and tumour cell resistance to therapy. Cancer cells depend on glycolysis and often have high rates of glucose uptake; therefore, hyperglycemia in itself may promote malignant cell proliferation. It has also been suggested that glucose deprivation may induce cytotoxicity (glucotoxic generation of reactive oxygen species and DNA damage).

[8,65,66]

The reduced risk for prostate cancer in diabetic men, could be due to the lower level of plasma androgens (testosterone) in type 2 diabetic men. Higher androgen levels are known to be associated with an increased risk of prostate cancer. Furthermore, a genetic mechanism could be involved. Some genes may be involved in both, type 2 diabetes and prostate cancer. In the case of HNF1B, a single common polymorphism provides a direct link. The risk allele for type 2 diabetes is protective for prostate cancer, and vice versa.

[67]

There are evidences of an association between overweight/obesity and an increased risk of cancers of the liver, gallbladder, pancreas, thyroid gland, breast, and colon and in lymphoid and haemopeietic tissue, breast (in postmenopausal women), colon/rectum, endometrium, adenocarcinoma of the oesophagus, and kidney. Obesity may also increase risk of mortality from some cancers, such as prostate. Adipose tissue produces a number of cytokines, predominantly IL-6, that may play a causative role in regulating mitogenic activity. Leptin is an adipocytokine, may be involved in local invasion and metastasis of established solid tumours. Adipose tissue produces free fatty acids, monocyte chemoattractant protein, PAI-1, and TNF-α. Each of these factors might play an etiologic role in regulating malignant transformation or some cancer progression. In some cases, the role of these molecules is well known. A high correlation has been observed between obesity, circulating oestrogen levels, and increased breast cancer risk, especially in postmenopausal women. These women usually present an increase in both estrone and estradiol, a likely consequence of the increased aromatase activity of the adipose tissue. Obesity is also associated with increased IGF-1 activity due to reduced levels of insulin growth binding proteins 1 and 2. Activation of IGF-1 receptors by IGF-1 or insulin, or both, is thought to have an important role in carcinogenesis. Adiponectin is an adipocytokine, whose plasma concentration is inversely associated with BMI. Adiponectin appears to exert an antiproliferative effect in breast cancer cell.

and IGF-I receptors. Insulin receptor may be expressed in two different isoforms, A and B, produced by an alternative splicing of the insulin receptor gene transcript [79]. In malignant cells, the A isoform expression is predominant [80]. Activation of isoforms A insulin receptor at variance with the isoform B insulin receptor elicits more mitogenic than metabolic effects [80]. Therefore, insulin may favour cancer progression and facilitate the growth of tumours [8]. When both the insulin and IGF-I receptor interact with their Copyright © 2014 John Wiley & Sons, Ltd.

[18,48,56,64]

[3]

[23]

[56,68]

[69] [3] [70] [56]

[8]

[71]

ligands, multiple signalling pathways are activated, which leads to phosphorylation of adaptor proteins such as the insulin receptor substrate family. These signalling pathways may promote proliferation, protection from apoptotic stimuli, invasion, and metastasis, potentially enhancing promotion and progression of many types of cancer cells [81]. Elevated levels of insulin have been shown to be a risk factor for a number of cancers. It was confirmed by meta-analysis [82], which shows excess risks of colorectal, Diabetes Metab Res Rev 2014; 30: 543–553. DOI: 10.1002/dmrr

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pancreatic, and breast cancers. Apart from direct effects of insulin on cancer cells, it is possible that hyperinsulinemia could promote carcinogenesis indirectly through its effects on IGF-1 [83]. High insulin levels have been shown in animals to stimulate IGF-I, which has been shown to increase the risk of colorectal cancer [25]. As mentioned earlier, cancer cells over-express insulin receptors and IGF-I receptors. Insulin reduces the hepatic production of insulin-like growth-factor-binding protein-1 (IGFBP-1) [84] and IGFBP-2 [85]. This leads to increased levels of circulating free, bioactive IGF-I. This could act as a growth stimulus in preneoplastic and neoplastic cells that express these receptors. It is to note that IGF-I has more potent mitogenic and anti-apoptotic activities than insulin [86]. People with circulating IGF-I have an increased risk of common epithelial cancers such as breast, colon, and prostate [87]. Prospective studies performed by The Endogenous Hormones and Breast Cancer Collaborative Group [88] have shown that women with the highest concentration of IGF-I were found to have a 28% higher risk of developing breast cancer than women with lowest concentration. In breast cancer, insulin induces P450 aromatase activity and reduces sex hormones binding globulin (SHBG); these increasing levels of free oestrogen in turn increase mitogenicity [89]. A meta-analysis of 43 prospective and cross-sectional studies indicated lower levels of SHBG and higher levels of oestrogen and testosterone amongst patients with type 2 diabetes, compared with controls, even after adjustment for obesity [48]. Elevated endogenous sex steroid levels are associated with a higher risk of postmenopausal breast, endometrial, and possibly other cancers [56]. Hyperinsulinemia may suppress prostate carcinogenesis by reducing levels of active IGF-I, a putative risk factor for prostate cancer [90]. Other explanations are possible. The reduction in risk of prostate cancer has been suggested as due to lower levels of testosterone in men with diabetes [91], as higher androgens levels are known to be associated with an increased risk of prostate cancer [92]. Tumour cells exhibit enhanced glucose metabolism compared with normal tissue. The altered metabolism of cancer cells characterized by high rates of glucose consumption and glycolysis was described by Otto Warburg 81 years ago [93]. Most diabetic patients present both hyperglycemia and hyperinsulinemia. Thus, it is difficult to distinguish the specific role of hyperglycemia in increasing cancer risk. Neoplastic cells use glucose for proliferation, and one of the central characteristics of malignant tissues is increased metabolism of glucose towards the pentose phosphate pathway [94]. Therefore, a higher circulating glucose concentration may foster cancer development by providing an amiable environment for the growth of malignant cell clones. Theories of cancer energetics focus on the role of glycolysis to generate adenosine triphosphate, which in turn fuels the high-energy requirements of tumour Copyright © 2014 John Wiley & Sons, Ltd.

L. Szablewski

growth. The recent resurgence of interest in the Warburg hypothesis and cancer energetics emphasizes the dependence of many cancers on glycolysis for energy, creating a high requirement for glucose, because ATP generation by glycolysis requires far more glucose than oxidative phosphorylation. Hypoxia is one of the hallmarks of cancer. The presence of hypoxia has been demonstrated in different types of solid tumours. Thus, it has been hypothesized that hyperglycemia drives mitogenic activity. However, evidence suggests that this is not the case as most cancers have highly effective upregulated, insulin-independent glucose uptake mechanisms and therefore may not derive a further growth advantage from hyperglycemia. Beyond glucotoxic generation of reactive species and DNA damage, hyperglycemia may supplement the effect of hyperinsulinemia [95]. Glucose deprivation may induce oxidative stress and glucotoxicity. Therefore, further evidence suggests a role for the oxidative stress-responsive genes that are sensitive to hyperglycemia and regulate the level of reactive oxygen species (ROS) [65]. The metabolic abnormalities that characterize diabetes mellitus increase oxidative stress and cause permanent pro-inflammatory conditions. This state reduces intracellular anti-oxidant capacity, predisposing susceptible cells to malignant transformation. High concentrations of free radicals and oxidants generate a potent ROS that can damage cell DNA, causing mutations. ROS may also react with other cellular molecules such as proteins and lipids, forming derivative products. These products may alter intracellular homeostasis that predispose for accumulation of mutations that contribute to the carcinogenesis process [96].

The influence of glucose-lowering therapies on cancer risk Insulin is required for all patients with type 1 diabetes, and it is also necessary for many patients with type 2 diabetes to treat hyperglycemia. Insulin and IGF-1 and their receptors and their intracellular signalling pathways share large similarities. Likewise, the metabolic and mitogenic effects of the two hormones partially overlap [3]. Both insulin and analogue insulins, by stimulating the insulin and IGF-1 receptors, can function as growth factor stimulating mitogenesis [97]. Several formulations of insulin exist: short-acting human regular insulin, intermediate-acting human neutral protamine Hagedorn insulin, and both rapidacting and long-acting analogues of human insulin [98]. It was demonstrated that modification of the molecular structure of insulin could result in increased mitogenic properties in cell lines and animal models [3]. A series of widely publicized epidemiologic analyses examined a possible association between insulin use and/or use of long-acting Diabetes Metab Res Rev 2014; 30: 543–553. DOI: 10.1002/dmrr

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insulin analogue glargine [99–101]. Insulin glargine may have a disparate impact on cancer risk through its binding to IGF-1 receptors [102,103]. There have been four large retrospective observational studies looking into possible causal link [3]. The study examined the analogue insulins glargine, aspart, and lispro and human insulin. It was found a dose-dependent increased risk of malignancy with insulin glargine compared with human insulin [104] and also a higher rate for breast cancer in patients receiving insulin glargine monotherapy relative to those on insulin glargine combined with other insulin preparations [105]. On the other hand, randomized clinical trial data from a 5-year trial of insulin glargine versus neutral protamine Hagedorn insulin did not evidence of excess cancer risk in the insulin glargine arm [106]. Also, other observations showed no evidence of increased cancer risk in patients receiving insulin glargine relative to insulin-naïve patients [3,107]. It was no evidence of an increased risk of cancer associated with insulin detemir [3,108] (Table 3). The biguanide metformin is the most commonly used therapy in patients with type 2 diabetes. It has been reported to reduce cancer risk or cancer mortality when compared with untreated patients [109]; however, these

studies have generally been limited in their ability to assess association with specific cancer types. Recent studies in human breast cancer cells showed that in vitro metformin inhibited cell proliferation, reduced colony formation, and caused partial cell cycle arrest [117]. The possible mechanism for the anti-cancer effect of metformin is stimulation in tumour cells of AMP-activated protein kinase (AMPK) and its upstream regulator liver kinase B1 (LKB1), a well-recognized tumour suppressor protein [118]. Activators of AMPK act as antiproliferative agents because they reduce insulin and IGF-1 signalling downstream of the receptor and therefore, inhibit insulin-stimulated proliferation [119]. Unfortunately, the anti-cancer effects of metformin in breast cancer have not been matched in prostate cancer patients, as studies have shown that the use of metformin was not associated with lowering of risk cancer [120] (Table 3). Thiazolidinediones are insulin-sensitizing drugs. The drugs in this class are peroxisome proliferator-activated receptor (PPAR)γ agonists, and in vitro studies indicate that PPARγ agonists have several anti-cancer activities. They inhibit growth and induce apoptosis as well as cell differentiation. Data on the insulin-sensitizing drug are

Table 3. The influence of glucose-lowering therapies on cancer risk Anti-diabetic drugs Insulin

Metformin

Sulphonylureas

Thiazolidinediones

Mechanisms of action

References

Insulin therapy increases the risk of colorectal or pancreatic cancer, but did not influence the risk of breast or prostate cancer. No differences between in overall cancer progression between human insulin and insulin analogues were observed. Both insulin and analogue insulins, by stimulating the insulin and IGF-1 receptors, can function as growth factors stimulating mitogenesis. Several observational studies suggest a possible association of insulin therapy with increased risk of developing cancer. Insulin analogues such as insulin glargine have been implicated, possibly due to its higher binding affinity for the IGF-1 receptor and therefore higher mitogenic potency than human insulin or other analogues.

[101]

Treatment of type 2 diabetic patients with metformin is associated with reduced risk of cancer or cancer mortality. Metformin has been shown to inhibit cellular transformation and selectively kill cancer stem cells in genetically different types of breast cancer. It promotes apoptosis in cancer cells. Metformin use by ovarian cancer patients with type 2 diabetes was associated with improved survival; patients had longer progression-free survival. In epithelial cells, metformin-induced AMP kinase activation has been shown to active growth inhibitory and protein synthesis pathways. Activation of AMP kinase strongly suppresses cell proliferation in both malignant and non-malignant cells.

[109,110]

Some studies suggest an increased risk of malignancies in type 2 diabetic patients treated with different sulphonylureas. These drugs are associated with a similar pattern of risk as insulin. Although it is possible that the association of sulphonylureas and cancer risk is genuine, it is difficult to determine whether the findings reflect excess cancer amongst users of the sulphonylureas or reduced risk in those using comparator drugs.

[47,101]

In vitro studies indicate that thiazolidinediones have several anti-cancer activities, such as inhibiting growth and inducing apoptosis and cell differentiation, although some animal data suggest PPAR agonist may potentiate tumorigenesis. Treatment with pioglitazone for more than 12 months was associated with a 40% increased risk for bladder cancer. May be it is a possible link between prolonged use of pioglitazone and an increased risk for bladder cancer. On the other hand, a significant protective effect was found for breast cancer in pioglitazone group compared with the control group receiving placebo. Definitive human data on cancer risk associated with thiazolidinediones are not available. Therefore, it is possible that this class of drugs may increase, decrease, or have a neutral effect on the risk in cancer or cancer progression in humans.

[115,116]

Copyright © 2014 John Wiley & Sons, Ltd.

[47,97]

[111,112] [113] [114]

[56]

[3] [2] [56]

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Table 4. Single nucleotide polymorphisms consistent with an association between diabetes mellitus and cancer Cancer Breast Colorectal Pancreatic Prostate

Single nucleotide polymorphisms

Ref.

rs5945326 (DUSP9), rs12518099 (CETN3), rs7578597 (THADA) rs11249433 (NOTCH2) rs7578597 (THADA), rs864745 (JAZF1), rs5219 (KCNJ11), rs7961581 (TSPAN8, LGR5) rs4402960 (IGFBP2), rs1801282 (PPARγ)a rs8050136 (FTO), rs1387153 (MTNR1B) rs757210 (HNF1B/TCF2)b rs864745 (JAZF1), rs10923931 (NOTCH2)b, rs11708067 (ADCY5)b, rs9939609 (FTO)b, rs10811661 (CDKN2A/B)b,c, rs7903146 (TCF7L2)b,c, rs231362 (KCNQ1)b,c, rs10830963 (MTNR1B)c,

[130] [131] [15] [16] [10] [23] [132]

a

Diabetic patients had a decreased risk for colorectal cancer. Association for prostate cancer is in the inverse direction. Loci associated with altered β-cell dysfunction or impaired insulin release and could result in less insulin production, thus blunting effects in increasing prostate cancer risk [129].

b c

more controversial. The different effects have been reported for different types of cancer [8]. It is possible that thiazolidinediones may increase [121], decrease [122], or have a neutral effect [123] on the risk of cancer or cancer progression in humans. Definitive human data on cancer risk associated with thiazolidinediones are not available [56] (Table 3). Sulphonylureas, the other group of anti-diabetic drugs, are secretogagues. They stimulate β-cells to release insulin and cause hyperinsulinemia. These drugs can cause hypoglycemia and weight gain. Because these drugs cause hyperinsulinemia, they have been associated with an increased risk of cancer [124]; however, different sulphonylureas may have different effects, for example, glyburide being more deleterious than gliclazide [125]. A small number of observational studies found a higher risk of cancer or cancer death amongst individuals with diabetes treated with sulphonylureas compared with those treated with other diabetes medications [100,105,124]. Drugs of incretin-based therapies enhance or mimic the effect of gut-derived incretin hormones [98]. The first of this class of drugs is liraglutide, which is an analogue of human glucagon-like peptide-1 (GLP-1). In rodent studies, liraglutide increased risk of medullary thyroid cancer. To date, there is no evidence of a causal relationship between liraglutide and human medullary thyroid cancer [126]. Wolf et al. [127] suggest that GLP-1 and exenatide, the other homolog of human GLP-1, are inhibitors of breast cancer proliferation. There is some evidence from

one small study of transgenic rodent model that suggests that sitagliptin, an inhibitor dipeptidyl peptidase-4 (DPP-4), may be associated with pancreatic cancer, especially with pancreatic ductal hyperplasia [128].

Conclusion There is a growing body of epidemiologic evidence supporting a link between diabetes and the incidence of some cancers. Mechanisms by which obesity, hyperglycemia, hyperinsulinemia, and inflammation interact with cancer risk require further study. It is also clear that the benefits of anti-diabetic therapy outweigh any possible risk of neoplasia. Furthermore, a genetic mechanism could be involved. Some genes may be involved in both, type 2 diabetes and cancer (Table 4).

Acknowledgements This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Conflicts of interest The author has no conflicts of interest.

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